The proposed studies aim to characterize, in behaving animals, aspects of a cognitive-limbic-motor circuit that is relevant to the pathophysiology of schizophrenia and other affective and cognitive disorders. The emphasis of the circuit is on the convergence, in the nucleus accumbens (NAc), of dopaminergic projections from the ventral tegmental area (VTA) and glutamatergic projections from the prefrontal cortex (PFC), hippocampus, and amygdala. The NAc is a region believed to serve as an interface for cognitive and affective regulation of behavior. Our working hypothesis is that PFC modulation of the information transfer to the NAc from the VTA and from limbic temporal lobe regions such as amygdala and hippocampus, is essential for the translation of cognitive and emotive processes into appropriate motor responses. Abnormal PFC control of this information transfer, as may occur in a disease state, results in aberrant cognitive, affective, and motoric behaviors. In designing the experiments, we have used a """"""""functional systems"""""""" approach whereby the interaction of corticolimbic giutamatergic and VTA dopaminergic afferents to the NAc about is investigated in awake animals at the postsynaptic level by measuring unit recording, at the presynaptic level by measuring dopamine and glutamate release, and at a behavioral level by quantitating stereotypy and locomotion. The specific hypothesis to be tested is that the PFC regulates hippocampal and amygdalar modulation of glutamate and dopamine release, and of neuronal activity, in the NAc of behaving animals. We will investigate this mode of PFC regulation in normal animals and in two distinct animal models of schizophrenia that are associated with PFC-dependent behavioral abnormalities. Although the direct PFC regulation of dopamine release or neuronal activity in the NAc has been the subject of intense study, the nature of PFC involvement in modifying the influence of other key regions on NAc function in behaving animals remains unclear. Hence, the proposed experiments will provide novel information on (1) the basic characteristics of corticolimbic regulation of presynaptic and postsynaptic function in the NAc of behaving animals and (2) how disruption of PFC function modifies this regulation.
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